For unknown reasons, in the last 30 years, adenocarcinomas of the esophagus and gastric cardia have become the most rapidly increasing cancers. Estimated five year survival with these cancers is approximately10% and in African Americans, it is even lower. Reasons for disparate mortality are also unknown. Conversely, the incidence of squamous cell carcinoma of the esophagus has remained stable in most populations, although declines have also been reported. Recently identified risk factors include tobacco use and obesity. Chronically elevated levels of peptide hormones in the IGF-system, some with known mitogenic and antiapoptotic properties, have been implicated in the etiology of some cancers including breast, colon and prostate, and genetic factors may play a critical role in influencing circulating levels. Together with my mentors, we propose to utilize questionnaire and biological data from a US based, multi-center, population-based, case-control study of esophageal cancer comprising 466 participants for whom biological specimens are available. The specific aims of the proposed research are: 1) To evaluate the relationship between polymorphic variation in genes related to the IGF-system, (IGF1, GH1, and IGFBP3) and risk of adenocarcinomas of the esophagus and gastric cardia, 2) To determine whether polymorphic variation on candidate genes in Aim 1 influence five-year survival among cases, 3) To determine whether elevated plasma levels of peptides related to the IGF-system (IGF 1, IGF II, IGFBP3, and leptin) at diagnosis are associated with survival among patients diagnosed with adenocarcinoma of esophagus and gastric cardia, 4) To evaluate whether polymorphic variation in candidate genes in Aim 1 is associated with circulating levels of (IGF-I, IGF-II, IGFBP3 and leptin) among controls. The proposed project will provide a mentored career development opportunity in molecular epidemiology, and also further our understanding of the role of IGF-system related polymorphisms in the etiology of gastric cardia and esophageal adenocarcinoma.